Potential new treatments for inflammatory diseases of the airways including COPD were described, ranging from phase III trial data with GlaxoSmithKline’s PDE4 inhibitor, Cilomilast Arifl
Trang 11 COPD = chronic obstructive pulmonary disease; LPS = lipopolysaccharide; TNF- α = tumour necrosis factor-α.
Available online http://respiratory-research.com/content/2/5/E003
Introduction
The American Thoracic Society meeting is the largest
gathering of lung related specialists in the world
Approxi-mately 16,000 people from 79 different countries
attended the San Francisco meeting The meeting was
aimed at physicians, scientists and health care providers
and offered up-to-date information on clinical practice and clinical and basic research Among the topics covered were lung injury, asthma, allergy, chronic obstructive pul-monary disease (COPD), lung development, lung trans-plantation and gene expression in a programme containing more than 300 scientific and clinical symposia
Presenta-Meeting report
New approaches to the modulation of inflammatory processes in
airway disease models: ATS 2001, May 18–23, San Francisco
David J Hele
Respiratory Pharmacology Group, Cardiothoracic Surgery, Imperial College School of Medicine, National Heart and Lung Institute, London, UK
Correspondence: David J Hele, Respiratory Pharmacology Group, Cardiothoracic Surgery, Imperial College School of Medicine, National Heart and
Lung Institute, Dovehouse Street, London, SW3 6LY, UK Tel: +44 (0)207 352 8121 Ext 3042; fax: 0207-351-8126; e-mail: d.hele@ic.ac.uk
Abstract
The 97thAmerican Thoracic Society meeting proved to be an excellent meeting, providing a wealth of
new information on inflammatory diseases of the airways Once again there appeared to be an
increased emphasis on chronic obstructive pulmonary disease (COPD) with most of the major drug
companies concentrating a large part of their efforts in this field An assessment of the new British
Thoracic Society guidelines, which are designed to promote better management of COPD, was also
presented at the meeting Potential new treatments for inflammatory diseases of the airways including
COPD were described, ranging from phase III trial data with GlaxoSmithKline’s PDE4 inhibitor,
Cilomilast (Ariflo®) to the development of AstraZeneca’s novel dual dopamine D2-receptor/
β2-adrenoreceptor agonist, Viozan™ Of particular interest was Byk Gulden’s Ciclesonide, a new
corticosteroid with equivalent efficacy to the market leaders but with an improved safety profile The
same company also presented data on their PDE4 inhibitor, Roflumilast, which is now in phase II/III
Bayer presented data on their PDE4 inhibitor, BAY 19-8004, in a smoking animal model and claimed
greater anti-inflammatory efficacy than with a steroid Asta Medica (now known as Elbion) also
described a new potent PDE4 inhibitor, AWD 12-281, with anti-inflammatory activity In the
bronchodilator field, an analysis of data from a one-year trial with Boehringer Ingelheim’s Tiotropium
revealed a possible improvement in lung function in COPD patients; this needs to be confirmed in a
specifically designed study Inhibitors of p38 (c-Jun NH2-terminal kinase and syk kinase) were also
discussed as anti-inflammatory agents with potential in the treatment of COPD and asthma
GlaxoSmithKline’s p38 kinase inhibitor, SB 239063, appeared to be the most advanced of these with
clinical data expected in two to three years Lyn kinase was also discussed as a novel target for
inflammatory airway diseases
Keywords: airway diseases, animal models, chronic obstructive pulmonary disease, new approaches, new
treatments
Received: 1 June 2001
Revisions requested: 13 June 2001
Revisions received: 13 June 2001
Accepted: 14 June 2001
Published: 3 July 2001
Respir Res 2001, 2:E003
This article may contain supplementary data which can only be found online at http://respiratory-research.com/content/2/5
© 2001 BioMed Central Ltd (Print ISSN 1465-9921; Online ISSN 1465-993X)
Trang 2Respiratory Research Vol 2 No 5 Hele
tions of original research in all respiratory fields are always
a highlight of the meeting
Review
Dr D Halpin and Dr M Rudolf (The Royal Devon and Exeter
Hospital, Exeter, Devon, UK) on behalf of the British
Tho-racic Society COPD consortium presented an
assess-ment of the new British Thoracic Society guidelines, which
are designed to promote better management of COPD It
showed that in terms of therapy, the use of long-acting β2
-adrenergic bronchodilators and anticholinergics is still
increasing, whereas steroid use has not increased since
1997 The use of spirometry in diagnosis has increased
but is still much underused and advice on smoking
cessa-tion or its therapy does not appear to be widely available
to patients
New approaches
MA Birrell (Imperial College, London, UK) described a
murine model of lipopolysaccharide (LPS)-induced
neu-trophilic airway inflammation He showed that the mouse
has distinct advantages over the rat in that it provides the
opportunity to dissect the mechanisms involved in
inflam-matory responses using the molecular (transgenic and
gene knockout animals) and immunological (antibodies)
tools, which are more readily available for the mouse than
rat To further explore the advantages conferred by using
mice the same author also described the development
and partial characterisation of a model of elastase-induced
emphysema in the mouse This model may be of great use
to the many groups now seeking to study and develop
drugs for the treatment of COPD
Dr DC Underwood (GlaxoSmithKline, Philadelphia, USA)
described a short-term murine model of smoke inhalation
and outlined its use in the study of smoking-related
inflam-mation Mice were exposed to smoke for one to three days
and the inflammatory response was studied First he
demonstrated the development of an inflammatory
response and then showed that the resulting inflammation
could be inhibited by pretreatment with the selective p38
MAP kinase inhibitor, SB 239063 The data support the
use of this type of compound for the future treatment of
inflammatory lung diseases such as COPD
New treatments
Corticosteroids
Two posters, which generated a lot of interest, described
preclinical studies with Ciclesonide, a new corticosteroid
Dr M Belvisi (Imperial College, London, UK) outlined in
vivo data in the Brown Norway rat supporting the concept
that Ciclesonide is a prodrug, which when delivered
directly into the airways, can be transformed by esterase
cleavage into the active metabolite (R-M1) producing high
local anti-inflammatory activity The anti-inflammatory
effi-cacy of Ciclesonide in these studies was similar to that
produced by Fluticasone but with an improved safety profile, thus demonstrating an improved therapeutic ratio over Fluticasone These findings were supported by the findings of Dr D Bundschuh (Byk Gulden, Konstanz,
Germany) who, in a range of in vitro and in vivo studies,
demonstrated an improved safety margin with Ciclesonide when compared to Budesonide He also demonstrated the prodrug anti-inflammatory activity of Ciclesonide at the target organ Ciclesonide represents a corticosteroid with
an improved safety profile when compared to other corti-costeroids currently used in the treatment of inflammatory diseases of the airways A compound with this profile has great potential and its future development will be watched with interest
D 2 -receptor and β2 -adrenoreceptor agonist
Viozan™ (AR-68397AA), a novel dual dopamine D2 -recep-tor/β2-adrenoreceptor agonist, is being developed as a potential treatment for COPD Dr A Young (AstraZeneca,
Loughborough, UK) described work in vitro in guinea pig trachea and in vivo in the dog, demonstrating rapid onset
and long duration of action of the compound at both the
D2 and β2 receptors Two other presentations examined the component properties of Viozan™ Dr I Oakley (AstraZeneca, Loughborough, UK), using the D2-selective agonist AR-C65116AB and the β2-adrenoceptor agonist salbutamol, demonstrated in ovalbumin-sensitised Brown Norway rats that the D2 receptor agonist reduced tachy-pnoea, whereas the β2-receptor agonist improved lung function without affecting respiratory rate This suggests the combination of the two agonistic properties may provide greater benefit than either agonist in isolation
Dr M Trevisiani (University of Ferrara, Italy) described studies using a guinea pig spinal cord preparation and capsaicin-induced plasma leakage in rat trachea He showed that the D2-receptor agonists ropinirole and AR-C65116AB inhibit both central and peripheral neuropep-tide release, providing further evidence of the potential beneficial effects of these type of compounds in the treat-ment of inflammatory diseases of the airways
Anticholinergics
In two poster presentations Dr A Anzueto (University of Texas, San Antonio, USA) and Dr DP Tashken (University of California, Los Angeles, USA) presented results of an analy-sis of two large one year clinical trials with the anticholiner-gic bronchodilator, Tiotropium, given by inhalation at 18µg once daily to patients with COPD One-year studies of Tiotropium demonstrated a sustained bronchodilator effect, reduction in exacerbation frequency and improvement in
quality of life measures The post hoc analyses suggest that
the rate of lung function loss observed in placebo-treated patients might be mitigated in Tiotropium-treated patients, although such an effect of Tiotropium would require a specifically designed prospective trial
Trang 33
PDE4 antagonists
Results from a six-month phase III trial with the novel
selec-tive PDE4 antagonist Cilomilast (Ariflo®) in stable COPD
patients were reported at the meeting Placebo or Cilomilast
at 15 mg orally, twice daily, for 6 months was administered
to a total of 2058 patients Dr JD Edelson (GlaxoSmithKline,
Philadelphia, USA) demonstrated a sustained improvement
in lung function in COPD patients after treatment with
Cilomilast, and a reduction in the risk of exacerbations The
same author using the St Georges Respiratory
Question-naire (a questionQuestion-naire used to assess quality of life) also
reported an improvement in health status in the Cilomilast
treated group Dr CH Compton (GlaxoSmithKline,
Philadel-phia, USA) demonstrated that the compound was safe and
well tolerated in this large patient group Gastrointestinal
side effects in Cilomilast treated patients were generally
self-limited and mild to moderate in intensity In a separate
study in the clinic, Dr J Kelly (GlaxoSmithKline, UK) looked
at the possibility of interaction between Cilomilast and
theo-phylline and found no evidence of pharmacokinetic or
dynamic interaction and no cardiovascular interaction
In a study using human bronchial epithelial and sputum
cells, Dr G Chipappara (Institute of Respiratory
Patho-physiology, Italina national Research Council, Palermo,
Italy) demonstrated a reduction in the neutrophil
chemoat-tractants tumour necrosis factor-α (TNF-α), interleukin-8
and granulocyte-macrophage colony stimulating factor in
cells treated with Cilomilast This suggests that at least
part of the efficacy of Cilomilast in treating COPD patients
may rest with its ability to reduce neutrophilic
inflamma-tion Dr CA Owen (University of Utah, USA) demonstrated
that Cilomilast inhibits the migration of activated
neu-trophils and reduces their capacity to mediate extracellular
proteolysis These effects also support the use of the
compound in the treatment of COPD
A new addition to the PDE4 inhibitor field is Roflumilast, a
potent and selective compound from Byk Gulden Dr D
Bundschuh (Byk Gulden, Konstanz, Germany) presented
data in antigen-driven or LPS-driven rat airway
inflamma-tion models These studies showed that Roflumilast is
much more potent than Cilomilast at reducing cell
infiltra-tion, total protein and TNF-α concentration in
bronchoalve-olar fluid after antigen challenge, and some 310-fold more
potent than Cilomilast in inhibiting LPS-induced circulating
TNF-α These data were supported by studies conducted
by Dr L Wollin (Byk Gulden, Konstanz, Germany) and Dr
HG Hoymann (Fraunhofer Institute of Toxicology and
Aerosol Research, Hanover, Germany) who demonstrated
a reduction in airway hyperresponsiveness after
pretreat-ment with Roflumilast in an antigen-induced airway
hyper-responsiveness model in the rat These data suggest that
Roflumilast may provide a potential new candidate for the
treatment of chronic inflammatory disorders of the airways
such as asthma and COPD
Dr MF Fitzgerald (Bayer, Stoke Poges, UK) described work with a PDE4 inhibitor, BAY 19-8004, currently in phase II for asthma and COPD treatment In an acute cig-arette smoke exposure model in the guinea pig, BAY 19-8004 showed greater efficacy in reducing the resulting inflammation than the steroid, betamethasone These data suggest the model may be useful for the evaluation of alternative inflammatory concepts for the treatment of COPD
Dr H Poppe (Elbion, Dresden, Germany) described one further PDE4 antagonist, AWD 12-281, employing a dif-ferent angle of attack by looking at the effect of the com-pound on mucus secretion in the mouse and LPS-induced neutrophilia in the rat and domestic pig In COPD in man, bronchioles are filled with viscous mucus produced by goblet cells Secretion of serous mucus containing lysozyme is beneficial in dissolving mucus plugs AWD 12-281 increased the secretion of serous mucus in mouse trachea as well as reducing LPS-induced neutrophilia in rats and pigs
Kinase inhibitors
In a session on the role of protein kinases in airway inflam-matory diseases several speakers discussed target identi-fication, validation and the profiling of novel small molecule inhibitors in animal models Dr DW Hay (GlaxoSmithKline, USA) outlined work with the p38 kinase inhibitor, SB
239063, in models that represent different pathological aspects of COPD This compound reduced neutrophil infiltration, reduced inflammatory cytokine production (such as interleukin-6) and reduced matrix metallopro-teinase-9 activity thus supporting the therapeutic potential
of SB 239063 in the treatment of COPD Dr Hay stated that the compound should be in the clinic within two to three years
Dr GP Anderson (University of Melbourne, Australia) dis-cussed lyn tyrosine kinase as a possible target for inter-vention in the treatment of asthma lyn kinase has been shown to be a signal transduction intermediate involved in the production of various cytokines and although not present in T cells it has been shown to regulate the inflam-matory response and the influx of T cells Also, animals deficient in lyn kinase as a result of homozygous knockout have been shown to have an enhanced response to antigen challenge This evidence supports lyn kinase as a possible target in the treatment of asthma
Dr AJ Lewis (Signal, San Diego, USA) presented data with the c-Jun NH2-terminal kinase antagonist, SP 600125
This compound is selective for c-Jun NH2-terminal kinase
1, 2 and 3 but is not orally available and is being tested as
a proof of concept molecule It showed good
anti-inflam-matory activity in a range of in vitro and in vivo screens
and is being followed up with a new lead compound, SPC
Available online http://respiratory-research.com/content/2/5/E003
Trang 4105, which has a good pharmacokinetic profile, is selective and orally active and may be useful in the treat-ment of inflammatory diseases of the airways Dr C Walker (Novartis, UK) rounded off the session with a talk on two undisclosed syk kinase inhibitors, again with a good anti-inflammatory profile aimed more at asthma than COPD
Conclusion
It was evident from this meeting that a great deal of effort
is going into research on the inflammatory aspects of dis-eases of the airways and that the greater part of that effort may now be directed towards potential treatments for COPD New animal models, which may be of great benefit
to study the mechanisms involved in the development of COPD, were described Many of the major drug compa-nies are looking for compounds that will modulate the inflammatory response The new developments showing some promise are the steroid with an improved safety profile (Ciclesonide), the PDE4 inhibitors (such as Cilomi-last and RoflumiCilomi-last), compounds that modify cytokine signal transduction via a specific kinase inhibitor and Viozan™, which provides a novel approach by combining
β2-adrenoreceptor agonist activity with dopamine D2 -receptor agonist activity to produce a long acting drug which is a bronchodilator and inhibits neuroinflammatory peptide release One other approach showing some promise is the use of the long acting anticholinergic, Tiotropium, which may slow the progressive decline in lung function that occurs with COPD This observation, however, needs to be confirmed in a specifically designed study In conclusion the American Thoracic Society meeting was again very successful, providing plenty of food for thought for both scientists and clinicians
Respiratory Research Vol 2 No 5 Hele